Process for the production of 6-phenyl-4-H-s-triazolo {8 4,3-a{9 {8 1,4{9 benzodiazepines

ABSTRACT

A process to make 6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepines by converting 2-(3-(hydroxymethyl)-4H-1,2,4triazol-4-yl)benzophenones to 2-(3-((phthalimido or methanesulfonyl)methyl)-4H-1,2,4-triazol-4-yl)benzophenones and converting these compounds to the highly active 6-phenyl-4H-striazolo(4,3-a)(1,4)benzodiazepines useful as tranquilizers and sedatives.

United States Patent Hester, Jr. Apr. 22, 1975 PROCESS FOR THEPRODUCTION OF 6-PHENYL-4-H-S-TRIAZOLO [56] References Cited[4,3-A1l1,4]BENZODIAZEPINES UNITED STATES PATENTS n r: Ja ks n 8- H str. Jr-. Galesbu g. 3,709.898 1 1973 Hester 260/308 R Mich.

73 Assignee; The Upjohn Company Kalamazom Primary Examiner-Alton D.Rollins Mich.

22 Filed: May 20. 1974 [571 ABSTRACT A process to make6-phenyl-4H-s-triazolol4.3- [211 Appl' 47l495 a][l,4]-benzodiazepines byconverting 2-[3- Related US. Application Data(hydroxymethyU-4l-l-l.2.4-triazol-4-yl]benzophenones [62] Division ofSer. No. 332.377. Feb. 14, 1973. I0 -I -HP 9r 'melhanesulfonyl)methyll-4H-l,2,4-triazol-4-yllbenzophenones and converting 52 0.5. 6.... 260/308R; 260/247.1; 260/247.5 E; these compounds to the highly active -p y260/268 MK; 260/283 R; 260/288 R;

Int. Cl C07d 57/02 Field of Search 260/308 Rtriazolo[4,3-a][1.4]benzodiazepines useful as tranquilizers andsedatives.

5 Claims, No Drawings PROCESS FOR THE PRODUCTION OF6-PHENYL-4-H-S-TRIAZOLO [4,3-A] [1,4JBENZODIAZEPINES This is a divisionof Application Ser. No. 332.377, filed Feb. 14, 1973.

BACKGROUND OF THE INVENTION Field of the Invention This invention isdirected to organic compounds and is particularly concerned with a novelprocess for the preparation of 6-phenyl-4H-s-triazolo[4,3-a][1.4]benzodiazepines and the intermediates thereof.

The novel process or production can be illustratively represented asfollows:

wherein A is selected from the group consisting of and o-i-ct-t whereinR 1 is selected from the group consisting of hydrogen, alkyl of 1 to 3carbon atoms, inclusive, phenyl, benzyl, and COOR wherein R is alkyldefined as above; and wherein R R R and R are selected from the groupconsisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive,halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, and alkanoylamino. in which the carbonchain moieties are of l to 3 carbon atoms, inclusive, and dialkylaminoin which alkyl is defined as above.

The intermediates corresponding to formula II are specifically claimed.

The process of this invention comprises: treating a2-[3-(hydroxymethyl)-4H-1,2,4-triazol-4- yl]benzophenone (1 with eithermethanesulfonyl chloride in the presence of a base (e.g. triethylamine,

or other volatile tertiary amine, at -40 to l0 C. to obtain the compound11 wherein A is or treating 1 with phthalimide and triphcnylphosphine inthe presence of a hydrogen acceptor e.g. diethyl azodicarboxylate togive the compound 11 wherein A is The compound of formula II (A is isthen treated with gaseous ammonia, preferably in the presence of analkali iodide, between 10 to 50 C. to give the compound III.

The compound of formula 11 wherein A is is treated with hydrazinehydrate in a lower alkanol l to 3 carbon atoms) for one to five hours at25-100 to give the corresponding compound of formula III above.

DESCRIPTION OF THE PREFERRED EMBODIMENT Alkyl groups of l to 3 carbonatoms, inclusive, are exemplified by methyl, ethyl, propyl, andisopropyl.

The carbon chain moiety of alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, dialkylamino which is of 1 to 3 carbon atoms, inclusive,is defined as lower-alkyl of 1 to 3 carbon atoms, inclusive, as above.

The alkanoylamino group of l to 3 carbon atoms consists of formamido Incarrying out the process of this invention a selected compound 1,preferably dissolved in an organic solvent is treated withmethanesulfonyl chloride in the presence ofa volatile, tertiary amine.Solvents useful in this reaction are chloroform, methylene chloride,ethylene dichloride, tetrahydrofuran, dioxane, mixtures thereof and thelike. As tertiary amine, triethylamine is preferred but any tertiaryamine with a boiling point below about 150C. and pK in the range ofabout 3 to about 5 can be used. The reaction is carried out at be tween40 to C., preferably between 20 and 0 C. The product 11 is recoveredfrom the reaction mixture by conventional means e.g. extraction with anorganic solvent such as chloroform, ether, methylene chloride or thelike. Vacuum distillation is used to remove the solvent and to obtainthe methanesulfonate Compound II is dissolved in an organic solvent e.g.tetrahydrofuran, dioxane, ether or the like, and treated with ammonia(gas) or hexamcthylenetetramine preferably after an alkali iodide, e.g.sodium or potassium iodide, has been added. After saturating thereaction mixture with ammonia, or after adding hexamethylenetetramine,the mixture is preferably stirred for from 4 to 48 hours at roomtemperature. The product III is obtained by conventional means, e.g.quenching the mixture, extraction, chromatography, crystallization, andthe like.

When the intermediate II is a phthalimido derivative, 0

the process consists of treating the starting material in a solvent withphthalimide in about equimolecular quantity or preferably with a slightexcess of 5-20 percent of the calculated amounts and an equimolecularamount of triphenylphosphine, and a hydrogen acceptor, for example, adialkyl azodicarboxylate, preferably diethyl azodicarboxylate. Thereaction is carried out at temperatures between 0-l00 C. In thepreferred embodiment of this reaction, temperatures between 2040 C. andstirring between 2-36 hours are used to complete the reaction. Solventsused are preferably water-free tetrahydrofuran, dioxane, 1 ,2-dimethoxyethane, ether, chloroform, methylene chloride and the like. Atthe termination of the reaction, the product 11 is recovered andpurified in conventional manner, e.g. concentrating the reactionmixture, extraction, chromatography and recrystallization.

This product 11 is then treated with hydrazine hydrate in a loweralkanol e.g. methanol, ethanol, l-propanol, or 2-propanol at atemperature of 25-100 C. for 1 to 5 hours. Preferably, the temperatureis kept between 65] 00 C. The product (111) is recovered and purified inconventional manner, e.g. extraction, chromatography crystallization andthe like.

The following examples and preparations are illustrative of theprocesses and products of the present invention, but are not to beconstrued as limiting. Preparation 1 2' Benzoyl-4-chloroacetanilideAcetyl chloride (81.3 g., 1.037 mole) was added to a stirred solution of2-amino-5-chlorobenzophenone (200.0 g., 0.864 mole) and pyridine (68.4g., 0.864 mole) in dry ether (4 1.); the mixture was kept at ambi enttemperature for 2 hours and treated with 500 ml. of water. The layerswere separated and the ether layer was dried over anhydrous sodiumsulfate and concentrated. Crystallization of the residue from ethylacetate- Skellysolve B hexanes gave: 124.0 g. of 2'-benzoyl-4-chloroacetanilide of melting point 114-115 C. Two

more crops of 2'-benzoyl-4-chloroacetanilide also were obtained: 67.8 g.of melting point 11315-1 14.5C.

and 33.0 g. of melting point 1l3l 14 C.

Preparation 2 6-Chloro-4phenyl-2( l H )-quinoline The procedure(reaction of 2-benzoyl-5- chloroacetanilide with sodium hydroxide) of A.E.

Drukker and C. I. Judd, J., Heterocyclic Chem. 3, 359

( 1966) was used for this preparation. The yield was 77 percent. Twoother preparations have been described.

S. C. Bell, T. S. Sulkowski, C. Gochman and S. J. Childress, J. Org.Chem. 27, 562 (1962); G. A. Reynolds,

C. R. Hauser, J. Amer. Chem. Soc. 72, 1852 (1950).

Preparation 3 2,6Dichloro-4-phenylquinoline The procedure of A. E.Drukker and C. l. Judd, J.

Heterocyclic Chem. 3, 359 (1966) was used for this preparation. Theyield was 62 percent.

Preparation 4 6-Chloro-2-hydrazino-4-phenylquinoline A stirred mixtureof 2,6dichloro-4-phenylquinoline (2.7 g., 0.01 mole) and hydrazinehydrate (6.8 g.) was refluxed under nitrogen for 1 hour and concentratedin vacuo. The residue was suspended in warm water, and the solid wascollected by filtration, dried and recrystallized from ethylacetate-Skelly B hexanes to give 1.81

g. (67%) yield) of 6-chloro-2-hydrazino-4- phenylquinoline of meltingpoint 156.5157 C.

' Anal. calcd. for C H ClN C, 66.79; H, 4.49; CI, 13.15; N, 15.58.Found: C, 67.15; H, 4.65; CI,

Preparation 5 7-Chloro-1-methyl-5-phenyl-striazolo[4,3-a]-quinoline Astirred mixture of 6-chloro-2-hydrazino-4- phenylquinoline (1.4 g.,0.0052 mole), triethyl orthoacetate (0.925 g., 0.0057 mole) and xyleneml.)

was refluxed, under nitrogen, for 2 hours 40 minutes.

During this period the ethanol formed in the reaction was removed bydistillation through a short, glass helixpacked column. The mixture wasconcentrated to dryness in vacuo and the residue was crystallized frommethanol-ethyl acetate to give: 1.28 g. of7-chloro-lmethyl-5-phenyl-s-triazolo[4,3-a]quinoline of melting point253.5255 C. (83.9% yield). The analytical sample was crystallized frommethylene chloride: methanol and had a melting point 252.5-253.5 C.

Anal. calcd. for C H ClN C, 69,50; H, 4.12; CI, 12.07; N, 14.31.

Found: C, 69.38; H, 4.02; CI, 12.10; N, 14.49. Preparation 65-Chloro-2-(3-methyl-4H-l,2,4-triazol- 4-yl)benzophenone (Oxidation of7-chlorol -methyl-5- phenyl-s-triazolo[4,3-a]quinoline) A stirredsuspension of 7-chloro-1-methyl-5-phenyls-triazolo[4,3-a]quinoline (2.94g., 0.01 mole) in acetone ml.) was cooled in an ice-bath and treatedslowly with a solution prepared by adding sodium periodate 2 g.) to astirred suspension of ruthenium dioxide (200 mg.) in water (35 ml.). Themixture became dark. Additional sodium periodate (8 g.) was added duringthe next 15 minutes. The ice bath was removed and the mixture wasstirred for 45 minutes. Additional sodium periodate (4 g.) was added andthe mixture was stirred at ambient temperature for 18 hours andfiltered. The solid was washed with acetone and the combined filtratewas concentrated in vacuo. The residue was suspended in water andextracted with methylene chloride. The extract was dried over anhydrouspotassium carbonate and concentrated. The residue was chromatographed onsilica gel (100 g.) with 10 percent of methanol-90 percent ethylacetate; 50 ml. fractions were collected. The product was eluted infractions -20 and was crystallized from ethyl to give: 0.405 g. ofmelting point l68-169.5 C. and 0.291 g. of melting point 167.5-169 (23.4percent yield) of 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone. The analytical sample hada melting point of 168 C.

Anal. calcd. for C H ClN O:

C, 64.54; H, 4.06; CI, 11.91; N, 14.11.

Found: C, 64.56; H. 4.35; CI, 11.97; 11.93; N, 14.29. Preparation 75-Chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yllbenzophenone A stirred mixture of5-chloro-2-(3-methyl-4H-1,2,4- triazolo-4yl)benzophenone, (2.98 g., 0.01mole) paraformaldehyde (3 g.) and xylene 100 ml.) was warmed undernitrogen, in a bath maintained at 125 C. for 7 hours. The mixture wasthen concentrated in vacuo. The residue was chromatographed on silicagel 150 g.) with 3 percent methanol-97 percent chloroform. Fiftyml.fractions were collected. The product was eluted in fractions -44. Thefractions were concentrated and the residue was crystallized fromethanol-ethyl acetate to give: 1.64 g. of5-chloro-2-[3-(hydroxymethy1)-5-methyl-4H-1,2,4-triazol-4-yllbenzophenone, of melting point 138l42 C.;0.316 g. of melting point 138.5141 C.; and 0.431 g. of melting point139-l41 C., (72.8 percent yield). The analytical sample had a meltingpoint of l38l39 C.

Anal. calcd. for C, H ClN O C, 62.30; H, 4.30; Cl, 10.81; N, 12.82.

Found: C, 62.23; H, 4.22; CI, 10.82; N, 11.73. Preparation 82-(o-Chlorobenzoyl)-4- chloroacetanilide In the manner given inPreparation 1, 2-amino-2',5- dichlorobenzophenone, acetyl chloride andpyridine were reacted in ether to give 2'-(o-chlorobenzoyl)-4-chloroaeetanilide.

Preparation 9 6-chloro-4-(o-chlorophenyl)-2( l H quinoline In the mannergiven in Preparation 2, 2'-(ochlorobenzoyl)-4'-ehloroacetanilidc wasreacted with sodium hydroxide to give 6-chloro-4-(o-chlorophenyl)-2(1H)-quinolone. Preparation 10 chlorophenyl)quinoline In themannergiven by A. E. Drukker and C. I. Judd, .1. Heterocyclic Chem. 3, 359(1966), 6-chloro-4-(ochlorophenyl)-2-( lH)-quinolone was chlorinated togive 2.6-dichloro-4-(o-chlorophenyl)quinoline. Preparation 1 16-ehloro-2-hydrazino-4-(ochlorophenyl)quinoline In the manner given inPreparation 4, 2,6-dichloro-4- (o-chlorophenyl)quinoline was heated withhydrazine hydrate to give6-chloro-2-hydrazino-4-(ochlorophenyl)'quinoline.

Preparation 12 7-chlorol -methyl-S-(o-chlorophenyls-triazolo[4,3-a]quinoline In the manner given in Preparation 5,6-chloro-2- hydrazino-4-(o-chlorophenyl)quinoline and triethylorthoacetate in xylene wererefluxed to give 7-chloro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3- alquinoline.

Preparation 13 2,5-dichloro-2-(3-methyl-4H-1,2,4-triazol-4-y1)benzophenone In the manner given in Preparation 6,7-chloro-1- methyl-5-(o-chlorophenyl)-s-triazolo[4,3-alquinoline inacetone was oxidized with sodium periodate and ruthenium dioxide to give2,5-dichloro-2-(3-methyl-4H- 2,6-dichloro-4-(o-1,2.4-tria2olo-4-yl)benzophenone of melting point 147.5-148.5 C.

Anal. calcd. for C H Cl N O:

C, 57.85; H, 3.34; CI, 21.35; N, 12.65.

Found: C, 57.70; H, 3.21; Cl, 21.58; N. 12.47. Preparation 142',5-dichloro-2-[3-(hydroxymethyl)-5- methy1-4H- l ,2,4-triazol-4-yllbenzophenone In the manner giver in Preparation 7, 2',5-dichloro-2-(3-methyl-4H-l ,2,4-triazol-4-yl )benzophenone was treated at C. inxylene with paraformaldehydc to give2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yllbenzophenone of melting point 193.5 C.

1n the same manner given in the prior Preparations other startingcompounds of formula 1 can be made. Representative compounds thusobtained include: 2-chloro-5-nitro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl lbenzophenone;5-chl0ro-2-[3-(hydroxymethyl)-5-ethyl-4H-1,2,4-triazol-4-yl]benzophenone;5-chloro-2-[3-(hydroxymethyl)-5-phenyl-4H-1,2,4-triazol-4-yl]benzophenone; 5-chloro-2-[ 3-(hydroxymethyl )-5-benzyl-4H-l,2,4- triazol-4-yllbenzophenone;2',6-difluoro-5-(methylthio)-2-[3-hydroxymethyl)-5- propyl-4H- l,2,4-triazol-4-yllbenzophenonc;5-bromo-2'-chloro-2-[3-(hydroxymcthyl)-4H-1,2,4-triazol-4-yl]benzophenone;2'-chloro-5-fluoro-2-[3-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]bcnzophenone;

2 '-chloro-6-cyano-2-[ 3-( hydroxymethyl )-5-carbomethoxy-4H-1,2,4-triazol-4-yllbenzophenone;2-chloro-4-diethylamino-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone;

2 '-chloro-5-( methylthio )-2-[ 3-( hydroxymethyl )-5- methyl-4H-l,2,4-triazol-4-yl]benzophenone;2-chloro-3-formamido-2-[3-(hydroxymethyl)-5-ethyl- 4H-l,2,4-triaz0l-4-yllbenzophenone;2'-chloro-4-(ethylsulfinyl)-2-[3-(hydroxymethyl)-5-phenyl-4H-1,2,4-triazol-4-yl]benzophenone;2-chloro-5-(propylsulfonyl)-2-[3-(hydroxymethyl)-5- carbopropoxy-4H-1,2,4-triazol-4-yllbcnzophenone;

1,2,4-triazol-4-yl lbenzophenone; 2'-(dimethylamino)-4-isopropyl-2-[3-(hydroxymethyl )-4H-1 ,2,4-triazol-4-yl]benzophenone;2-chloro-4,5-dicyano-2-[3-(hydroxymethyl)-5- methyl-4H-l,2,4-triazol-4-yllbenzophenone;3-(ethylsulfinyl)-3,5-dipropyl-2-[3-hydroxymethyl)-5-methyl-4H-l,2,4-triazol-4-yl]benzophenone;5-chloro-2-acetamido-2-[3-(hydroxymethyl)-5- methyl-4H- 1,2,4-triazol-4-yl]benzophenone;5-chloro-2-[3-(hydroxymethyl)-4H-1,2,4-triazol-4- yl]benzophenone;2'-chloro-2-[3-hydroxymethyl)-4H-1,2,4-triazol-4- yl]benzophenone;

2',5-dichloro-2-[ 3-(hydroxymethyl)-4H-1 ,2,4-triazol-4-yl]benzophenone;

2-[ 3-(hydroxymethyl)-4H-l ,2,4-triazol4- yl]benzophenone;

2-[ 3-(hydroxymethyl)-5-methyl-4H-1 ,2,4-triazol-4- yl]benzophenone; andthe like.

EXAMPLE 1 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3- a][1,4]benzodiazepine A solution of 0.328 g. (1.00 mmol.) of -chloro-2-[3-(hydroxymethyl )-5 methyl-4H-l ,2,4-triazol-4- yl]benzophenone dissolvedin 5.0 ml. hydrocarbonstabilized-chloroform was cooled to 20 C. in a DryIce acetone bath, treated with 0.206 ml. (0.150 g., 1.5 mmol.) oftriethylamine and stirred for 5 minutes. The solution was treateddropwise with 0.106 ml. 1.3 mmol.) of mcthanesulfonyl chloride andstirred for minutes. Ammonia gas was introduced to the atmosphere abovethe cold solution. Immediately a white precipitate appeared. Stirringwas maintained at 20 C. for 10 minutes after which the temperature wasgradually raised to 25 C. After 20 minutes, 3 ml. of freshly distilledtetrahydrofuran and 0.332 g. (2.00 mmol.) of potassium iodide was addedand the resulting mixture was stirred overnight (24 hrs.). The reactionmixture was quenched in a 5 percent aqueous so dium hydroxide solution,extracted with chloroform, dried over anhydrous sodium sulfate andconcentrated in vacuo to yield an oil. On trituration with ethylacetate, fine, white needles of 8-chloro-1methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine were deposited. This wasrecrystallized from ethyl acetate to yield 30 mg. of white needles ofmelting point 228230 C. and mg., of melting point 2l5-223.

Instead of ammonia hexamethylenetetramine can be used.

EXAMPLE 2 S-Chlorol -methyl-6-( o-chlorophenyl)-4H-striazolo[4,3-a}[1,4]benzodiazepine A suspension of 0.363 g. (1.00mmol.) of 2',5- dichloro-2-[ 3-( hydroxymethyl )-5-methyl-4H-l ,2,4-triazol-4-yl]benzophenone in 5.0 ml. of methylene chloride was cooled toC. in a Dry Ice/acetone bath and treated with 0.206 ml. (0.150 g., 1.50mmol.) of triethylamine, followed by dropwise addition of 0.106 ml. (1.3mmol.) of methanesulfonyl chloride. (Most of the starting materialdissolved during the addition of the methanesulfonyl chloride.) During15 minutes the temperature was gradually raised to 0. The reactionmixture was quenched on ice and extracted with methylene chloride. Theorganic extracts were treated with a saturated aqueous sodiumbicarbonate solution, dried over anhydrous sodium sulfate andconcentrated in vacuo to yield an oil. The oil was dissolved in 5 ml. offreshly distilled tetrahydrofuran in a dry flask and treated first with0.332 g. (2.00 mmol.) of potassium iodide, then ammonia (gas). Aftersaturating the reaction mixture with ammonia, the mixture was warmed toroom temperature (22-24 C.) and stirred for 24 hours. The mixture wasquenched in a saturated aqueous sodium hydroxide solution, extractedwith chloroform, dried over anhydrous sodium sulfate and concentrated invacuo to afford an oil. Crystallization from ethyl acetate andmethanol/ethyl acetate yielded 25 mg. of a tan solid of melting point 2l022 1 C. Recrystallization from ethyl acetate gave pure8-chloro-1-methyl-6-(o-chlorophenyl)-4l-I-striazolo[4,3-a][1,4]benzodiazepineof melting point' EXAMPLE 35-Chloro-2-[3-(phthalimidomethyl)-5-methyl-4H-l,2,4-triazol-4-yljbenzophenone.

A stirred mixture of 5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (0.656

g., 0.002 mole), phthalimidc (0.324 g., 0.0022 mole), triphenylphosphine(0.576 g., 0.0022 mole) and dry tetrahydrofuran (20 ml.), undernitrogen, was treated with diethyl azodicarboxylate (0.383 g., 0.0022mole) and stirred at ambient temperature for 23 hours. It wasconcentrated in vacuo and the residue was chromatographed on silica gelg.) with 1.5 percent methanol 98.5 percent chloroform; 10 ml. fractionswere collected. The product was eluted in fractions 31-57 andcrystallized from methanol-ethyl acetate to give 0.148 g. of5-chloro-2-[3-(phthalimidomethyl)-5-methyl-4H-l,2.4-triazol-4-yl]benzophenone of melting point 2l7.52l9 C.: 0.257 g.of product of melting point 2l9220; 0.189 g. of melting point 2l8.5220C. and 0.082 g. of melting point 219220.5 of 5-chloro-2-[3-(phthalimidomethyl)-5-methyl-4H-1,2,4-triazolcan be prepared from3-amino-3,4-dihydro-4-hydroxy- 4-phenylquinazolines of formula IV byallowing a compound of formula IV to react with an activated derivativeof phthaloylglycine, e.g. the acid chloride, mixed anhydride orimidazolide, and then warming the resulting product in acetic acid togive a compound of formula II, A is The 3-amino-3,4-dihydro-4-hydroxy-4-phenylquinazolines (IV) may be prepared as described in the literaturefor 3amino-6-chloro-3,4-dihydro-4- hydroxy-4-phenylquinazoline by M. E.Derieg et al., J. Org. Chem. 36,782 (1971):

IV 1 X'C'CHI'N 2. Hole N o CHg'l wherein R R R R and R have the samesignificance as in formula 11, wherein X is Cl. Br.

and wherein A is EXAMPLE 4 5-Chloro-2-[3-(phthalimidomethyl)-5-methyl-4l1,2,4-triazol-4-yl ]benzophenone A stirred solution of phthaloylglycine(2.26 g., 0.01 mole) in dry tetrahydrofuran ml.), under nitrogen, wascooled in an ice-bath and treated with carbonyldiimidazole. This mixturewas kept at ambient temperature (2224) for 1.5 hours, cooled in an icebath and treated with a mixture of 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline (2.88 g., 0.01 mole) intetrahydrofuran (25 ml.). This mixture was kept at ambient temperaturefor 42 hours and concentrated in vacuo. The residue was mixed with adilute sodium bicarbonate solution and extracted with methylenechloride. The extract was washed with a saturated sodium chloridesolution, dried over anhydrous sodium sulfate and concentrated to give acrude oil. This oil was mixedwith acetic acid (50 ml.) and warmed in anoil bath at 120 for 1 hour. The acetic acid was then concentrated invacuo and the residue was mixed with water, neutralized with sodiumbicarbonate and extracted with methylene chloride. The extract waswashed with water, dried over anhydrous sodium sulfate and concentrated.The residue was chromatographed over-silica gel (400 g.) with 2.5percent methanol-97.5 percent chloroform. The product obtained from thecolumn was crystallized from methylene chloride-ethyl acetate to give0.24 g. of 5-chloro-2-[3- (phthalimidomethyl)5-methyl-4H-1,2,4-triazol-4- yl]benzophenone of melting point 2 l 52 1 8 C. An additional 0.135 g. of this product of melting point 2l6-2l8.5 C. wasobtained by working up the mother liquors.

EXAMPLE 5 8-Chlorol -methyl-6-phenyl-4H-s-triazolo[4,3-a]1,4]benzodiazepine A stirred mixture of 5-ehloro-2-[3-(phthalimidomethyl )5-methyl-4H-l ,2,4-triazol-4- yllbenzophenone (0.257g.. 0.562 mmole) and absolute ethanol (3 ml.) was treated with hydrazinehydrate (0.05 ml.. 1.04 mmole) and warmed in an oil bath at 73 C. forminutes. (The solution precipitated a white solid after 30 minutes.) Thecooled mixture was mixed with water and extracted with chloroform. Theextract was washed with brine, dried over anhydrous sodium sulfate andconcentrated. The residue was chromatographed on silica gel (42 g.) with2 percent methanol-98 percent chloroform; 10 ml. fractions werecollected. The product was eluted in fractions 33-57 and crystallizedfrom ethyl acetate to give 77 mg., of melting point 229230 C. and 26mg.. of melting point 228229.5 C. of 8-chloro-l-methyl-6-phenyl-4H-s-triazolo[4.3-a][ I .4]benzodiazepine.

Anal. calcd. for C H, ClN,:

C. 66.13; H. 4.24; Cl, 11.48; N, 18.15.

Found: C, 66.05; H. 4.13; Cl. 11.34; N, 18.00.

EXAMPLE 6S-Chloro-l-methyl-6-(2.6-difluorophenyl)-4H-striazolo[4,3-a][1.4]benzodiazepineIn the manner given in Example 1, 2,6'-difluoro-5- chloro-2-[ 3-(hydroxymethyl )-5-methyl-4Hl ,2,4- triazol-4-yllbenzophenone was treatedwith methanesulfonyl chloride and triethylamine in chloroform. Theresulting solution was then treated with ammonia (gas) to give8-ch1oro-l-mcthyl-6-(2,6- difluorophcnyl)-4H-s-triazolo[4,3- a1,4]benzophenone.

EXAMPLE 7 8-Chloro-6-phenyl-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine 1nthe manner given in Example 1, 5-chloro-2-[3- (hydroxymethyl )-4H-l.2,4-triazol-4-yl lbenzophenone was treated with methancsulfonylchloride and triethylamine in chloroform. The resulting solution wasthen treated with ammonia (gas) to give 8-chloro-6-phenyl-4H-s-triazolo[4,3-a'][1,4]benzophenone.

EXAMPLE 8 6-(o-chlorophenyl)-4H-s-triazolo[4,3-

a][ l ,4]benzodiazepine in the manner given in Example 1,2'-chloro-2-[3- (hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone wastreated with methanesulfonyl chloride and triethylamine in chloroform.The resulting solution was then treated with ammonia (gas) to give 6-(0-chlorophenyl)-4H-s-triazolo[4,3-

a][ 1,4]benzophenone.

EXAMPLE 98,10-Dicyano-l-methyl-6-(m-nitrophenyl)-4H-striazolo[4,3-a][1,4]benzodiazepine1n the manner given in Example 1, 3,5-dicyano-3-nitro-2-[3-(hydroxymethyl)-5-methyl-4l-1-l ,2,4-triazol-4-yllbenzophenone was treated with methanesulfonyl chloride andtriethylamine in chloroform. The resulting solution was then treatedwith ammonia (gas) to give8,l-dicyano-l-methyl-6-(m-nitrophenyl)-4H-striazolo[4.3-a][1,4]benzophenone.

EXAMPLE l0 l-ethyl-8-bromo-6-( 2,4-diethylphenyl)-4H-striazolo[4,3-a][1.4]benzodiazepine In the manner given in ExampleI, -bromo-2',4- diethyl-2-[3-(hydroxymethyl)-5-ethyl-4H-1,2,4-triazol-4-yl]benzophenone was treated with methanesulfonyl chloride andtriethylamine in ehloroform. The resulting solution was then treatedwith ammonia (gas) to give l-ethyl-8-bromo-6-(2,4-diethylphenyl)-4I-I-s-triazolo[4,3- a[ l .4]benzophenone.

EXAMPLE I l l-Benzyl-8-trifluoromethyl-6-(o-chlorophenyl )4H-striazolo[43-a][1,4]benzodiazepine In the manner given in Example I,S-trifluoromethyl- 2-chloro2-[ 3-( hydroxymethyl )-5-benzyl-4H-I ,2,4-triazol-4-yllbenzophenone was treated with methanesulfonyl chloride andtriethylamine in chloroform. The resulting solution was then treatedwith ammonia (gas) to givel-benzyl-8-trifluoromethyl-6-(oehlorophenyl)-4H-s-triazolo[4,3- a] I l,4lbenzophenone.

EXAMPLE I2 I -Propyl-9-( ethylsulfonyl )-6-[p-(diethylamino)phenyl]-4H-s-triazolo[4,3- a][ 1,4 lbenzodiazepine In themanner given in Example 1, 4-(ethylsulfonyl)-4-(diethylamino)-2-[3-(hydroxymethyl)-5-propyl-4H-I.2,4-triazol-4-yl]benzophenone was treated with methanesulfonylchloride and triethylamine in ehloroform. The resulting solution wasthen treated with ammonia (gas) to give l-propyl-9-(ethylsulfonyl)-6-[p-(diethylamino)phenyl]-4H-s-triazolo[4,3- a][ 1,4]benzophenone.

EXAMPLE I3 I -Phenyl 7-propyl-6-( o-bromophenyl )-4H-striazolo[4,3-a][1,4]benzodiazepine In the manner given in Example I, 6-propyl-2-bromo-2-[3-( hydroxymethyl )-5-phenyl-4H-l ,2,4-triazol-4-yl]benzophenone was treated with methanesulfonyl chloride andtriethylarnine in chloroform. The resulting solution was then treatedwith ammonia (gas) to givel-phenyl-7-propyl-6-(obromophenyl)-4H-s-triazolo[4,3- a][ l,4]benzophenone.

EXAMPLE l48-nitro-I-methyl-6-(o-chlorophenyl)-4H-striazolo[4,3-a][1,4]benzodiazepineIn the manner given in Example 3, a mixture of 5-nitro-2-chlor0-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yllbenzophenone, phthalimide and triphenylphosphine intetrahydrofuran was treated with diethyl azodiearboxylate to give5-nitro-2-ehloro-2-[3- (phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.

In the manner given in Example 4, 5-nitro-2'-chloro-2-[3-(phthalimidomethyl)-5-methyl-4I-I-1,2,4-triazol- 4-yl]benzophenonewas heated in ethanol with hydrazine hydrate to give8-nitro-l-methyl-6-(o- 1 2 chlorophenyl )-4H-s-triazolo[4,3- a][1,4benzodiazepine.

EXAMPLE l5 EXAMPLE l6 8-Methylthiol -methyl-6-( o-ehlorophenyl)-4H-striazolo[4,3-a][1,4]benzodiazepine In the manner given in Example3, a mixture of 5- methylthio-2,-chloro2-[ 3-( hydroxmethyl )-5-methyl-4H-l,2,4-triazol-4-yllbenzophenone, phthalimide and triphenylphosphinein tetrahydrofuran was treated with diethyl azodiearboxylate to give5-methylthio-2- chloro-2-[3-(phthalimidomethyl)-5-methyl-4I-I-1 ,2,4-triazol-4-yl]benzophenone.

In the manner given in Example 5, 5-methylthio-2- ehloro-2-[ 3-(phthalimidomethyl)-5-methyl-4H-l ,2,4- triazol-4-yl]benzophenone washeated in ethanol with hydrazine hydrate to giveS-methylthio-1-methyl-6-(ochlorophenyl)-4I-I-s-triazolo[4,3-'

a] 1,4]henzodiazepine.

EXAMPLE I 7 l-Phenyl-9-ethoxy-8-isopropyl-6-Im-(methylthio)phenyl]-4H-s-triazolo[4,3- a] 1,4]benzodiazepine In themanner given in Example 3, a mixture of 4- ethoxy-5-isopropyl-3'-methylthio-2-[ 3- (hydroxymethyl )-5-phenyl-4II- l ,2,4-triazol-4-yllbenzophenone, phthalimide and triphenylphosphine in tetrahydrofuranwas treated with diethyl azodicarboxylate to give 4-ethoxy-5-isopropyll3'-methylthio-2- [3-(phthalimidomethyl )-5-phenyl-4 H-1 ,2,4-triazol-4-yl]benzophenone.

In the manner given in Example 5, 4-ethoxy-5- isopropyl-3'-methylthio-2-[ 3-( phthalimidomethyl )-5 phenyl-4H-I,2,4-triazol-4-yllbenzophenone was heated in ethanol with hydrazinehydrate to give I- phenyl-9-ethoxy-8-isopropyl-6-[m- (methylthio)phenyl]-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine.

EXAMPLE '1 8 1-propyl-8-isopropylsulfonyl-6-( o-fluorophenyl)-4H-striazolo[4,3-a][ 1,4]benzodiazepine.

In the manner given in Example 3, a mixture of 5-isopropylsulfonyl-2-fluoro-2-{ 3-(hydroxymethyl )-5propyl-4I-I-I,2,4-triazol-4-yl]benzophenone, phthalimide andtriphenylphosphine in tetrahydrofuran was treated with diethylazodiearboxylate to give 5-isopropylsulfonyl-Z-fluoro-2-[3-(phthalimidomethyl)- 5-propyl-4H-I,2,4-triazol-4-yl]benzophenone.

In the manner given in Example 5. a solution ofisopropylsulfonyl-2-fluoro2-[3-(phthalimidomethyl)-5-propyl-4H-l,2,4-triazol-4-yl]benzophenone in methanol was heated withhydrazine hydrate to give 1-propyl-8-isopropylsulfonyl-6-(o-fluorophenyl)-4I-l-striazolo[4,3-a][1.4]benzodiazepine.

EXAMPLE l9 EXAMPLE8-chloro-1-methyl-6-(o-chlorophenyl)-4H-striazolo[4,3-a] I,4lbenzodiazepine In the manner given in Example 3, a mixture of 2,5-dichloro-2-[ 3-(hydroxymethyl )-5-methyl-4H- l ,2,4-triazol-4-yl]benzophenone, phthalimide and triphenylphosphine intetrahydrofuran was treated with diethyl azodicarboxylate to give2,5-dichloro-2-[3- (phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone of melting point 262265 C.

Anal. calcd. for C H CI N O C, 61.11; H, 3.28; CI, 14.43; N, 11.40.

Found: C, 60.77; H, 3.26; Cl, 14.49; N, 11.45.

In the manner given in Example 4, 2,5-dichloro-2[3-(phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4- yl]benzophenone washeated in ethanol with hydrazine hydrate to give8-chloro-l-mcthyl-6-(o-chlorophenyl)-4H-s-triaZolo[4,3-a][1,4]benzodiazepine of melting point 223-225 C.

Varying the method in which A of compound III is a methanesulfonyl groupby using for the step II III a substituted amine produces open-chainbenzophenones of the formula V wherein R,. R R R and R have the samesignificance as in formula II and wherein R and R are alkyl of 1 to 3carbon atoms. inclusive, or together is a heterocyclic amine. e.g.pyrrolidino, 4- methylpiperazino, piperidino. or morpholino. Theresulting compounds also have tranquilizing and sedative activity indosages of 0.1 to 5 mg./kg.

EXAMPLE 21 5-Chloro-2-[ 3-methyl-5-( pyrrolidinomethyl )4H-1,2.4-triazol-4-yllbenzophenone A solution of 0.328 g. (1.00 mmol.) of5-chloro-2-[3- methyI-S-(hydroxymethyl)-4H-1,2,4-triazozl-4-yl]benzophenone dissolved in 5.0 ml. of methylene chloride was cooled to0 C. in an ice bath. Triethylamine (0.150 g., 1.5 mmol.) was added andthe solution was stirred for 5 minutes at 0 C. Cautiously, and dropwiseover 4 minutes, 0.106 ml. (1.3 mmol.) of methanesulfonyl chloride wasadded and the solution was stirred for 20 minutes. The reaction wasquenched on ice and extracted with a saturated aqueous sodiumbicarbonate solution, dried over anhydrous sodium sulfate andconcentrated in vacuo. The resulting oil, dissolved in 4.0 ml. offreshly distilled tetrahydrofuran, was treated at 0 C. with 0.332 g.(2.0 mmol.) of potassium iodide followed by 1.0 ml. of pyrrolidine. Themixture was stirred at 0 C. for 10 minutes then warmed to roomtemperature and stirred overnight. The mixture was quenched in anaqueous 5 percent sodium hydroxide solution and the product wasextracted with chloroform. The chloroform layer was dried over anhydroussodium sulfate and concentrated in vacuo to yield a yellow oil whichcrystallized from ethyl acetate to afford 200 mg. of5-chloro-2-[3-r'nethyl-5- (pyrrolidinomethyl)-4I-l-1,2,4-triaZ0l-4-yl]benzophenone in the form of fine white needles of melting point174176 C.

Anal. calcd. for C ,H ClN O:

C, 66.22; H, 5.56; N, 14.7]; CI, 9.31.

Found: C, 65.96; H, 5.62; N, 14.68; Cl, 9.31.

EXAMPLE 22 methylpiperazino)methyl]-4I-I-1,2,4-triazol-4-yl]benzophenone, oxalate salt 7 A solution of 1.312 g. (4.00 mmol.) of5-chloro-2-[3- methyI-S-(hydroxymethyl)-4I-I-1,2,4-triazo1-4-yl]benzophenone, dissolved in 20 ml. of methylene chloride, was cooledto 0 C. and treated with 0.825 ml. (6.00 mmol.) of triethylamine.Methanesulfonyl chloride (0.424 ml., 5.5 mmol.) was added dropwise overa period of 5 minutes via a syringe and the resulting solution wasstirred for 20 minutes. The solution was dissolved in additionalmethylene chloride and extracted with ice-water followed by an aqueoussodium bicarbonate solution. The organic layer was dried over anhydroussodium sulfate and concentrated in vacuo to yield an oil. The oil wasdissolved in 20 ml. of tetrahydrofuran, cooled to 0 C. and treated with1.33 g. (8.0 mmol.) of potassium iodide followed by 4.0 ml. ofl-methylpiperazine. The mixture was quenched in a cold percent aqueoussodium hydroxide solution and extracted twice with chloroform. Thechloroform extracts were combined, washed with water, dried overanhydrous sodium sulfate and concentrated in vacuo to yield a yellowoil. The oil was crystallized with difficulty as an oxalate salt bytreating with 1 g. of oxalic acid in ml. of ethanol. followed by coolingto 0 C. An amorphous solid (1.7 g., m.p. 190192 C. decomp.) wasobtained. An analytical sample had a melting point 190-191 C. (decomp.).

Anal. calcd. for C H ClN O (COOH)- C. 49.45; H, 4.45; N, 10.30; Cl,5.21.

Found: C, 49.32; H, 4.52; N. 10.82; Cl. 5.33.

EXAMPLE 23 5-Chloro-2-[3-methyl-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yllbenzophenone.

In the manner given in Example 21, 5-chloro-[3-methyl-S-(hydroxymethyl)4H-1,2,4-triazol-4- yl]benzophenone was reactedwith methanesulfonyl chloride in the presence of triethylamine and theresulting solution, treated with gaseous dimethylamine in the presenceof potassium iodide, to give 5-ehloro-2-[3- methyl-5-[ (dimethylamino)methyl ]-4H-1 ,2,4-triazol- 4-yl1benzophenone of melting point l71l72.

EXAMPLE 24 8-Chlorol -methyl-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine 5-Chloro-2-[3-[(methylsulfonyloxy)methy1]-5-methyl-4H-l ,2,4-triazol-4-y1]benzophenone (5 g.) (see Example 1),dissolved in water-free tetrahydrofuran, was treated with 4 g. ofhexamethylenetetramine 1 g. of potassium iodide and 20 ml. of ethanol.The mixture was refluxed for hours, then cooled, filtered, and thefiltrate evaporated to dryness to give a yellow gum. The gum wasdissolved in chloroform, the chloroform solution extracted with waterthen chromatographed over 300 g. of Silica Gel and 3 percent methanol-97percent chloroform. Fractions 52-132 gave a colorless oil which uponrecrystallization from ethylacetate gave 800 mg. of8-chloro-1-methyl-6-phenyI-4H-s-triazolo- [4,3-a][ 1 ,4]bcnzodiazepine\I claim:

I. A process for the production of a6-pheny1-4H-striazolo[4,3-a][1,4]benzodiazepine of the formula 111 oxy,alkylthio, alkylsulfinyl, alkylsulfonyl, and alkanoylamino in which thecarbon moiety is between 1 to 3 carbon atoms, inclusive, anddialkylamino in which alkyl is defined as above, which comprises:treating a compound of formula I:

' n on wherein R,, R R R and R are defined as above, in a mixture withphthalimide and triphenylphosphine in an inert water-free organicsolvent with diethyl azodicarboxylate between a temperature of 0 to Cfor a period of 2 to 36 hours; extracting the mixture and recovering thethus obtained phthalimido compound of formula [I wherein R R R R and Rare defined as above and wherein A is treating compound 11, in analkanol of 1 to 3 carbon atoms, inclusive, with hydrazine hydrate at atemperature between 25-l00 C. to obtain the compound of formula 111above.

2. The process of claim 1 in which the inert, waterfree organic solventis tetrahydrofuran and the reaction temperature is between 20-40 C.

3. The process of claim 1 wherein the alkanol of 1 to 3 carbon atoms,inclusive, is ethanol.

4. The process of claim 1, wherein the starting material is5-chloro-2-[3-(hydroxymethyl)-5-methy1-4H- l,2,4-triazol-4-y1]benzophenone.

5. The process of claim 1 wherein the starting material is2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl- 41-1-1,2,4-triazol-4-yl]benzophenone.

1. A PROCESS FOR THE PRODUCTION OF A6-PHENYL-4H-STRIAZOLO(4,3-A)(1,4)BENZODIAZEPINE OF THE FORMULA III
 1. Aprocess for the production of a6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine of the formula III 2.The process of claim 1 in which the inert, water-free organic solvent istetrahydrofuran and the reaction temperature is between 20*-40* C. 3.The process of claim 1 wherein the alkanol of 1 to 3 carbon atoms,inclusive, is ethanol.
 4. The process of claim 1, wherein the startingmaterial is5-chloro-2-(3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl)benzophenone.